1. Pathogen-sugar interactions revealed by universal saturation transfer analysis
- Author
-
Buchanan, Cj, Gaunt, B, Harrison, Pj, Yang, Y, Liu, J, Khan, A, Giltrap, Am, Le Bas, A, Ward, Pn, Gupta, K, Dumoux, M, Tan, Tk, Schimaski, L, Daga, S, Picchiotti, N, Baldassarri, M, Benetti, E, Fallerini, C, Fava, F, Giliberti, A, Koukos, Pi, Davy, Mj, Lakshminarayanan, A, Xue, X, Papadakis, G, Deimel, Lp, Casablancas-Antràs, V, Claridge, Tdw, Bonvin, Amjj, Settentau, Qj, Furini, S, Gori, M, Huo, J, Owens, Rj, Schaffitzel, C, Berger, I, Renieri, A, GEN-COVID Multicenter Study, Naismith, Jh, Baldwin, Aj, Davis, Bg, and Study, GEN-COVID Multicenter
- Subjects
Multidisciplinary ,SARS-CoV-2 ,Cryoelectron Microscopy ,Bristol BioDesign Institute ,UNCOVER ,COVID-19 ,Genetic Variation ,Covid19 ,Protein Domains ,Polysaccharides ,Max Planck Bristol ,Host-Pathogen Interactions ,Spike Glycoprotein, Coronavirus ,Sialic Acids ,Humans ,General ,Nuclear Magnetic Resonance, Biomolecular ,Protein Binding - Abstract
Many pathogens exploit host cell-surface glycans. However, precise analyses of glycan ligands binding with heavily modified pathogen proteins can be confounded by overlapping sugar signals and/or compounded with known experimental constraints. Universal saturation transfer analysis (uSTA) builds on existing nuclear magnetic resonance spectroscopy to provide an automated workflow for quantitating protein-ligand interactions. uSTA reveals that early-pandemic, B-origin-lineage severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike trimer binds sialoside sugars in an “end-on” manner. uSTA-guided modeling and a high-resolution cryo–electron microscopy structure implicate the spike N-terminal domain (NTD) and confirm end-on binding. This finding rationalizes the effect of NTD mutations that abolish sugar binding in SARS-CoV-2 variants of concern. Together with genetic variance analyses in early pandemic patient cohorts, this binding implicates a sialylated polylactosamine motif found on tetraantennary N-linked glycoproteins deep in the human lung as potentially relevant to virulence and/or zoonosis.
- Published
- 2022